This invention relates to a process for the chemical separation of stereoisomers. More particularly, this invention relates to a process of using a chiral acid for resolving mixtures of enantiomers of primary amines that are useful in the synthesis of (+)-physostigmine and (-)-physostigmine.
The cholinergic neuronal system can be found in the central nervous system (CNS), in the autonomic nervous system, and in the skeletal motor system. Acetylcholine (ACh) is the neurotransmitter in all ganglia, the neuromuscular junction, and the post-ganglionic synapses of the cholinergic nervous system. Acetylcholine is normally an excitatory neurotransmitter that binds to nicotinic and muscarinic receptors.
Acetylcholinesterase (ACHE) is an enzyme that hydrolyres and thereby deactivates ACh after it binds to a receptor. This enzyme is present in all peripheral and central junctional sites and in certain cells of the body.
In some circumstances, it is desirable to stimulate acetylcholine receptors. One method involves the use of indirect agonists, such as anticholinesterase drugs, which inhibit the hydrolysis of ACh by ACHE. When an anticholinesterase drug blocks AChE and inhibits the destruction of released ACh, a higher neurotransmitter level and increased biological response result. The alkaloid, physostigmine, which can be isolated from the seeds of the Calabar bean, has been found to be particularly effective as an anticholinesterase drug. Physostigmine has a high affinity for AChE and is capable of inhibiting AChE for prolonged periods.
It is believed that degeneration of the cholinergic pathways in the CNS and the resultant development of apparent irregularities in neuron arrangement may be a principal cause of senile dementia of the Alzheimer type. This disease leads to progressive regression of memory and learned functions. Since the average age of the population is on the increase, the frequency of Alzheimer's disease is increasing and requires urgent attention.
It has been suggested that cholinergic agonists, such as the anticholinesterase drugs, are useful in the treatment of Alzheimer's disease. Nevertheless, drug treatment with anticholinesterase drugs has not proved entirely satisfactory. Thus, there is a need in the art for new forms of drugs for the treatment of this disease.
The enantiomers of physostigmine are under investigation for the treatment of Alzheimer's disease. In order to satisfy the need for physostigmine enantiomers having the highest pharmaceutical activity, there exists a need in the art for a process for preparing the enantiomers. Specifically, the enantiomer (-)physostigmine is of current interest, and while methods for preparing physostigmine have been proposed, there exists a need in the art for a stereoselective process for producing the S- or (-)-form.
It has been found that the compound 1,3-dimethyl-5-methoxyoxindolylethylamine is an important intermediate in a recently discovered method of synthesizing (-)-physostigmine. While this amine can be prepared using conventional techniques, a racemic mixture is usually formed. Resolution of the racemic amine mixture into its R and S components would make it possible to synthesize (+)-physostigmine and (-)-physostigmine.
Resolution of mixtures of enantiomers, however, is very much a matter of trial and error. Even experienced investigators find that certain compounds resist chemical resolution by any one of a number of combinations of resolving agents and reaction conditions. As a general rule, investigators in the art of separating stereoisomers commence a study by using reagents and conditions that have been found to be successful in the past in resolving similar compounds.
A racemic mixture of the compound 1,3-dimethyl-5-ethoxyindolylethylmethylamine is known in the art. The racemic mixture has been resolved by the successive actions of d-camphor-sulphonic acid and d-tartaric acid. Julian et al., J. Chem. Soc., (1935), 755-757. Even though this compound bears a structural resemblance to the compound 1,3-dimethyl-5-methoxyindolylethylamine, which is the intermediate used in the synthesis of (.+-.)-physostigmine, application of the same strategy to a racemic mixture of the latter compound has not been successful, thus confirming the unpredictability of chemical resolution techniques.
Thus, in addition to the need for stereoselective methods for producing enantiomers of physostigmine, there also exists a need in the art for methods for preparing intermediates for use in the stereoselective process. The method should make it possible to obtain the intermediates in a state of high optical purity. In addition, the process should be easy to carry out and should employ reagents that are readily available.